Integration of Long-Term-Memory-Related Synaptic Plasticity Involves Bidirectional Regulation of Gene Expression and Chromatin Structure

• Published in: Cell Vol. 111; no. 4; pp. 483 - 493
• Main Authors: Guan, Zhonghui, Giustetto, Maurizio, Lomvardas, Stavros, Kim, Joung-Hun, Miniaci, Maria Concetta, Schwartz, James H., Thanos, Dimitris, Kandel, Eric R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.11.2002
• Subjects: Acetylation; Animals; Aplysia; CCAAT-Enhancer-Binding Proteins - genetics; CCAAT-Enhancer-Binding Proteins - metabolism; Chromatin - physiology; CREB-Binding Protein; Cyclic AMP Response Element-Binding Protein; FMRFamide - pharmacology; Gene Expression Regulation; Histone Deacetylases - genetics; Histones - genetics; Long-Term Potentiation - physiology; Long-Term Synaptic Depression - physiology; Motor Neurons - drug effects; Motor Neurons - physiology; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurons, Afferent - drug effects; Neurons, Afferent - physiology; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Serotonin - pharmacology; Synapses; TATA-Box Binding Protein - genetics; TATA-Box Binding Protein - metabolism; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/S0092-8674(02)01074-7

Excitatory and inhibitory inputs converge on single neurons and are integrated into a coherent output. Although much is known about short-term integration, little is known about how neurons sum opposing signals for long-term synaptic plasticity and memory storage. In Aplysia, we find that when a sensory neuron simultaneously receives inputs from the facilitatory transmitter 5-HT at one set of synapses and the inhibitory transmitter FMRFamide at another, long-term facilitation is blocked and synapse-specific long-term depression dominates. Chromatin immunoprecipitation assays show that 5-HT induces the downstream gene C/EBP by activating CREB1, which recruits CBP for histone acetylation, whereas FMRFa leads to CREB1 displacement by CREB2 and recruitment of HDAC5 to deacetylate histones. When the two transmitters are applied together, facilitation is blocked because CREB2 and HDAC5 displace CREB1-CBP, thereby deacetylating histones.